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Genetic ‘tour de force’ reveals worm’s workings

By Natasha McDowell

By simply feeding roundworms genetically-modified bacteria, UK scientists have conducted an extraordinary one-by-one analysis of the function of nearly 86 per cent of the worms 20,000 genes. US scientists have put the data to immediate use to search for genes that regulate fat storage.

The tiny Caenorhabditis elegans was the first animal to have its genome sequenced. However, identifying all its genes does not tell scientists how they control the animal’s development or behaviour.

So to reveal their function, biologists used the sequence information along with a technique called RNA-mediated interference (RNAi) to temporarily inactivate each of nearly 17,000 of the worm’s genes.

“It’s a tour de force of molecular genetics and a wonderful use of the full genome sequence,” says Paul Sternberg, at Caltech, California.

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“The power of the technique is incredible. It is the first time anybody has looked at the function of nearly every gene in an animal,” says Julie Ahringer at Cambridge University, UK, who led the study. She told New Scientist if the functions can be found for all the genes an animal has, the complex process of how they work together can be understood.

Furthermore, half the worm genes have human counterparts, so discovering the function of the worm’s genes will help explore what human genes do.

Bugs for dinner

In nature, RNAi acts as a defence mechanism to protect cells against retroviruses, but it has been cleverly adapted by researchers. The technique involves designing double-stranded RNA molecules that match a sequence in the RNA produced by the gene you want to inactivate. The molecules attach to the latter, targeting its destruction and thereby blocking the genes activity.

A quirk of the physiology of C. elegans means that such gene inactivation can occur simply if the RNAi molecule is eaten by the worm. And luckily for the researchers, the preferred diet of this little worm is the bug that for decades has been used in thousands of lab experiments – the bacterium E coli. Simply inserting the RNAi sequences into E coli and allowing the worms to feed resulted in the chosen gene being knocked out.

The technique is remarkably fast. “It used to take a year to knock out a gene, now with RNAi one person can knock-out every gene in just a few months,” says Ahringer.

Fluorescent fat

The data gathered can now be used to investigate particular biological processes, such as ageing or, as Gary Ruvkun at Harvard Medical School, Boston, and colleagues have now done, body fat storage.

Along with the RNAi molecules, the researchers included a fluorescent dye in the worm’s bug diet. This enables fat droplets in the intestinal cells of living worms to be visualised.

They then scoured the 17,000 inactivated genes to find those involved in regulating body fat. Over 300 genes were found that reduced the amount of body fat upon inactivation, and over 100 were identified that increased it. About 200 have human counterparts that may represent new targets for anti-obesity drugs.

“Mapping in the human genome is like navigating along the seashore and we have just placed 200 lighthouses. Human geneticists should take note,” says Ruvkun.